PROJECT SUMMARY: Urinary tract infections (UTIs) are highly prevalent (affecting over 15 million women annually in the United States), tend to recurrence and/or chronicity and are increasingly resistant to antibiotic treatment. Recent work suggests a ?Lock and Key? paradigm in which UTI susceptibility is governed by complex interactions of dynamic host susceptibility determinants and diverse bacterial urovirulence potentials that are driven not only by gene content but also by differences in the expression and regulation of conserved functions. Further, catheterization of the urinary tract increases susceptibility to infection by bacteria that do not usually cause UTIs in immunocompetent people, including highly antibiotic resistant strains such as methicillin resistant Staphylococcus aureus and Klebsiella pneumoniae, a prominent member of the carbapenem resistant Enterobacteriaceae. This proposal will assess the mechanisms by which urinary catheters affect acute UTI susceptibility and long-term pathophysiology in the urinary tract (UT). Short-term urinary catheterization increases the risk of UTI and other complications up to 80%, and prolonged catheterization increases the risk to 100%. In mouse models of catheter associated UTI (CAUTI), urinary catheterization itself results in the wounding of the bladder epithelium, leading to inflammation and fibrinogen release. Fibrinogen and other host proteins are deposited on catheters in both mice and human patients. Enterococcus, a common cause of CAUTI, binds this deposited fibrinogen via the EbpA adhesin to mediate catheter adherence, biofilm formation and UT colonization, even though Enterococcus cannot directly bind the catheter. This proposal tests the hypothesis that implanted catheters increase host susceptibility to UTI by diverse potential pathogens via wounding the uroepithelium, triggering inflammation and providing novel surfaces for bacterial binding. In addition, available data suggest that inflammation and epithelial wounding due to chronic cystitis remodels the bladder mucosa, rendering it more susceptible to subsequent infection. Continual wounding due to long-term catheterization may also result in bladder mucosal remodeling and increased infection susceptibility. This proposal aims to use histological, biochemical and genetic approaches in combination with representative mouse models and human clinical samples to: i) assess the effects of catheter implantation on infection susceptibility and determine host and bacterial factors important in CAUTI; ii) investigate the host proteins and diverse bacterial adhesins that mediate binding to and biofilm formation on implanted catheters and; iii) ascertain mucosal remodeling effects of prolonged foreign body residence in the UT. Understanding the mechanisms that contribute to the increased sensitivity to infection of the UT due to catheterization will give insights into the development of more effective therapies, which are sorely needed due to the spread of multidrug resistant uropathogens.